Ifosfamide is the INN designation for 3-(2-chloroethyl) -2-(chloroethylamino)-tetrahydro-2H-1,3, 2-oxazophosphorin-2-oxide. Ifosfamide is an important cytostatically active medication of the oxazaphosphorin type.
Ifosfamide is a white crystalline powder with a melting point of 48.degree. C. to 51.degree. C. and has strongly hygroscopic properties. Ifosfamide begins to sinter below the melting point and therefore has to be stored at temperatures that are as low as possible. It is also desirable to avoid contact with humidity whenever possible. Although ifosfamide dissolves to an extent of about 10 percent by weight in water, it is of only limited stability in aqueous solution. Hitherto ifosfamide has only been registered in formulations for parenteral use. Ifosfamide is available in the form of a sterile crystallizate which is dispensed in injection bottles in dosages of 200 mg to 2000 mg. Prior to administration, the sterile crystallizate must be dissolved in water for injection purposes, but it is required that the concentration not exceed 4%. This solution is suitable for intravenous injection. For purposes of short intravenous infusion the ifosfamide solution is dissolved in 500 ml Ringer's solution or similar injection fluids. The duration of infusion is about 30 minutes, possibly 1 to 2 hours. In the case of the 24-hour infusion, the ifosfamide solution is, for example, dissolved in a total of 3 liters of 5% dextrose-sodium chloride solution.
There are many problems associated with the manufacture and processing of ifosfamide. The manufacture of sterile crystallized ifosfamide produces a of changing physical characteristic. The variations on the free-flowing characteristics has a particularly deleterious effect on dosage accuracy when dispensing into injection vials.
The processing of ifosfamide is further impaired by its hygroscopicity and low melting point During longer storage periods the sterile crystallizate sinters and the speed of dissolution decreases. As ifosfamide begins to sinter, the clarity of the solution which can be obtained from it, and the pH value of the solution decrease and a yellow discoloration develops The medication then is generally no longer useful for therapeutic purposes.
Apart from the difficulties in manufacturing the sterile crystallizate, there are, above all, also serious disadvantages in use. Parenteral administration can only be performed by specialized medical personnel. The patient has to be admitted to hospital as an inpatient or must at least attend hospital every day for treatment. This involves a great deal of time on the part of staff and patient and added expense.
The potential danger of the substance necessitates extensive protective measures for the staff during the manufacture of the sterile injection solution from the dry substance. Parenteral therapy is unpleasant for a patient since he has to submit to a painful puncture during application and is connected to an infusion apparatus for the duration of the infusion.
Because of all these disadvantages there has long been a need for an oral dosage form which eliminates the above disadvantages. Oral administration could permit ambulatory therapy. Oral administration of ifosfamide would be pleasant for the patient and would no longer constitute a risk for the medical personnel.
All attempts to develop a solid oral dosage form have, however, failed because of the above-described physical-chemical properties of ifosfamide. In particular it was not possible to prepare a medicinal form in soft gelatin capsules. The active substance appears to react with the capsule wall, becomes tanned and the capsule no longer dissolves in the gastric juices. Similarly, many attempts to develop a tablet have hitherto failed. The substance adhered to the die of the tabletting machine, the tablets were too soft and the active substance sometimes spurted in liquefied form from the mold during compressing.